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European Journal of Heart Failure 2007 9(8):787-794; doi:10.1016/j.ejheart.2007.04.001
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© 2007 European Society of Cardiology

Anaemia and renal dysfunction are independently associated with BNP and NT-proBNP levels in patients with heart failure

Jochem Hogenhuisa, Adriaan A. Voorsa,*, Tiny Jaarsmaa, Arno W. Hoesb, Hans L. Hillegec, Johannes A. Kragtend and Dirk J. van Veldhuisena

a Department of Cardiology, Thoraxcenter, University Medical Centre Groningen, University of Groningen PO Box 30.001, 9700 RB Groningen, The Netherlands
b Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht Utrecht, The Netherlands
c Trial Coordination Centre, University Medical Centre Groningen, University of Groningen Groningen, The Netherlands
d Department of Cardiology, Atrium Medical Centre Heerlen, The Netherlands

* Corresponding author. Tel.: +0031 50 3611594. fax: +0031 50 3614391. E-mail address: a.a.voors{at}thorax.umcg.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Anaemia may affect B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels, but this has not been well described in heart failure (HF) patients without the exclusion of patients with renal dysfunction.

Aims: To study the influence of both anaemia and renal function on BNP and NT-proBNP levels in a large group of hospitalised HF patients.

Methods and results: We studied 541 patients hospitalised for HF (mean age 71±11 years, 62% male, and left ventricular ejection fraction 0.33±0.14). Of these patients, 30% (n=159) were anaemic (women: Hb <7.5 mmol/l, men: Hb <8.1 mmol/l). Of the 159 anaemic patients, 73% had renal dysfunction (eGFR<60 ml/min/1.73 m2) and of the non-anaemic patients, 57% had renal dysfunction. BNP and NT-proBNP levels were measured in all patients before discharge. In multivariable analyses both plasma haemoglobin and eGFR were independently related to the levels of BNP and NT-proBNP (standardised beta's of –0.16, –0.14 [BNP] and –0.19, –0.26 [NT-proBNP] respectively, P-values<0.01).

Conclusion: Anaemia and renal dysfunction are related to increased BNP and NT-proBNP levels, independent of the severity of HF. These results indicate that both anaemia and renal dysfunction should be taken into consideration during the interpretation of BNP and NT-proBNP levels in HF patients.

Key Words: BNP • NT-proBNP • Heart failure • Anaemia • Renal dysfunction

Received August 16, 2006; Revised December 22, 2006; Accepted April 5, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The diagnostic accuracy of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in patients who present at the emergency department with acute dyspnoea is well described [1,2]. However, even with optimal cut-off values determined by receiver operating characteristic curves, approximately 10% of the patients have false negative outcomes, and 16%-24% of the patients have false positive outcomes [1,2]. To further increase the diagnostic accuracy of these natriuretic peptides, it is important to identify other factors, beside the severity of HF, that influence BNP and NT-proBNP levels. We and others have previously described that, in addition to their correlation with severity of HF [3], both BNP and NT-proBNP levels are influenced by several other factors such as age, sex, obesity and renal function [4-10].

Another factor that might influence BNP and NT-proBNP levels in patients with HF is anaemia, which is relatively common in these patients. Since anaemia causes increased plasma volume independent of severity of HF [11], and because natriuretic peptides are released in response to ventricular plasma overload [12] it is conceivable that natriuretic peptide levels are higher in anaemic HF patients compared to non-anaemic HF patients. In 209 patients without HF or renal dysfunction Willis et al. recently demonstrated that NT-proBNP concentrations were significantly higher in patients with anaemia compared to patients without anaemia [13]. In contrast, in a subgroup analysis of the Breathing Not Properly trial, no correlation was found between BNP levels and haemoglobin in 200 patients with systolic HF, and only a weak correlation was found between BNP levels and diastolic HF [14]. However, in that study patients with renal dysfunction were excluded. To our knowledge, the independent influence of anaemia on NT-proBNP levels has never been investigated in an HF population without the exclusion of patients with renal dysfunction. Moreover, no evidence is available on the influence of anaemia and renal dysfunction on levels of both BNP and NT-proBNP in the same HF population. Since renal dysfunction is a well known cause of anaemia [15] and because it may influence both BNP levels and NT-proBNP levels by decreasing clearance [16], renal dysfunction should be taken into account when studying the effect of anaemia on BNP levels and NT-proBNP levels. Hence, the aim of the present study was to investigate the relationship between anaemia and BNP/NT-proBNP levels in a large group of HF patients with and without renal dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
The present study complies with the Declaration of Helsinki, the local ethics committee approved the research protocol and informed written consent was obtained from the subjects. All patients in the present study had been recently admitted for decompensated HF (NYHA II-IV) and were included in a multicentre HF trial conducted in The Netherlands (COACH) [17]. All participating sites (n=17) were experienced HF centre's. Patients were at least 18 years of age with evidence of structural underlying heart disease. Detailed information on the study design has been published before [17]. In short, COACH is a randomised controlled trial investigating the effect of education and counselling on readmission for HF and mortality. Of the 1049 patients included in the COACH study, 543 patients had NT-proBNP levels available at baseline, 601 patients had BNP levels available at baseline, and 541 patients had both BNP and NT-proBNP levels available at baseline. Main reasons for missing BNP data were: no Triage® BNP meter available and no facilities to store plasma samples at –80 °C (n=177), unplanned hospital discharge (n=75) or death during admission (n=20). Main reasons for missing NT-proBNP data were the following: the NT-proBNP substudy started after patients had already been included in COACH (n=272), no facilities to store plasma samples at –80 °C (one clinic; n=71), unplanned hospital discharge or logistical problems (n=155) and death during admission (n=9).

2.2. Measurement of BNP and NT-proBNP levels
Blood was collected shortly before discharge between 8:00 AM and 4:00 PM, after patients had been clinically stabilised and were considered well enough to go home. Prior to sampling patients were rested in the supine position, then 10 ml of whole blood was taken from an antecubital vein and collected into tubes containing potassium ethylenediaminetetraacetic acid (EDTA; 1 mg/ml blood). The tubes were centrifuged for 10 min (2500xg) and the plasma was separated and stored in polypropene tubes at –70 °C to –80 °C. The plasma samples were transported (on dry ice) to the Core Laboratory at the University Medical Centre Groningen, The Netherlands.

2.2.1. BNP measurement
In 364 out of the 541 patients, BNP levels were determined on site in whole blood within 4 h after blood collection. In 177 out of the 541 patients BNP levels were determined in plasma at the Core Laboratory. All measurements were performed using a fluorescence immunoassay kit (Triage®, Biosite Incorporated, San Diego, CA). Details on the system provided by the manufacturer indicated that the analytical sensitivity of the assay was less than 5.0 pg/ml. The system has been validated before [18]. The measurable range of the BNP assays was 5.0-5000.0 pg/ml.

2.2.2. NT-proBNP measurement
All measurements of NT-proBNP levels were performed in plasma at the Core laboratory on an Elecsys– 2010 analyser, a commercially available electrochemiluminescent sandwich immunoassay (Elecsys proBNP, Roche Diagnostics, Mannheim, Germany). The intra-assay precision (coefficient of variation) is 1.2-1.5%, and the inter-assay precision (coefficient of variation) is 4.4-5.0%, with an analytical range of 5-35,000 pg/ml [19].

2.3. Anaemia
The World Health Organisation definition of anaemia was used; Hb <7.5 mmol/l (12 g/dl) for women and Hb <8.1 mmol/l for men (13 g/dl) [20].

2.4. Renal function
Serum creatinine was determined from a blood draw shortly before discharge, in the local laboratory at each centre. Estimated Glomerular Filtration Rates (eGFRs) were calculated using the Levey-modified Modification of Diet in Renal Disease formula [21]: eGFR (ml/min/1.73 m2)=186xSCr–1.154xage–0.203x(0.742 if female)x(1.21 if black).

2.5. Left ventricular ejection fraction
Left ventricular ejection fraction (LVEF) data were available for 485 out of the 541 patients (90%), and were determined by echocardiography (83%), muga scan (14%) or gated spect (3%).

2.6. Boston score
For 501 out of the 541 patients with BNP and NT-proBNP levels available, the Boston score, a quantification related to severity of HF [22], was calculated by researchers who were blinded to BNP and NT-proBNP levels. This score was used in combination with LVEF to adjust possible determinants of BNP levels and NT-proBNP levels for severity of HF in the multivariable regression analysis. In short, the score consists of a medical history sub score (NYHA class, orthopnoea, dyspnoea during walking), a physical examination sub score (heart rate, central venous pressure, peripheral oedema, enlarged liver, rales, wheezing) and a chest radiography sub score (pulmonary congestion, cardiothoracic ratio). For each sub score, a maximum of 4 points is allowed. The diagnosis of HF is classified definite for a total score of 8-12 points, possible for a total score of 5-7 points and unlikely for a total score of 4 points or less. The Boston score was missing in 40 cases, since no chest radiography data were available for these patients.

2.7. Statistical analyses
In order to study the independent relationship between anaemia (haemoglobin [Hb]) and renal function (as expressed in the eGFR) with BNP and NT-proBNP levels, univariable and multivariable linear regression analyses were performed in the patient population with both BNP and NT-proBNP levels available (n=541). Because the BNP and NT-proBNP levels had a skewed distribution the natural logarithm was used to get an optimal residual analysis. To study potential confounding factors, the following variables were used in the univariable analyses (Pearson and Spearman correlation coefficients when appropriate) with BNP and NT-proBNP as the dependent variables: age, sex, LVEF, the Boston score, New York Heart Association (NYHA) functional class, HF aetiology, duration of HF symptoms, pulmonary congestion, rales, heart rate, systolic and diastolic blood pressure, presence of atrial fibrillation/flutter, haematocrit, renal disease, body mass index (BMI), hypertension, pulmonary embolism, chronic obstructive pulmonary disease or asthma, diabetes mellitus (type 1 and 2), and heart failure medication at admission and at discharge (diuretics, ACE inhibitors/angiotensin II receptor blocker, beta-blockers). Besides Hb and eGFR, a univariable P-value<0.15 was required to enter a variable into the stepwise multivariable linear regression analyses. When a multivariable P-value was >0.05 a variable was removed from the multivariable model. NT-proBNP or BNP levels were presented in bar charts stratified by quintiles of Hb. To get more insight in the distribution of NT-proBNP and BNP across the ranges of Hb, ANOVA trend analyses were performed for NT-proBNP or BNP after these were stratified by quintiles of Hb. The associations of the anaemia and renal function with NT-proBNP and BNP were presented in bar charts. Outcomes were considered significant when P<0.05. Values are presented as means±SD except when stated otherwise. All analyses were performed with SPSS version 11.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Study populations
Demographic and clinical characteristics of the 541 patients with both BNP and NT-proBNP data available are presented in Table 1. The mean age of these 541 patients was 71 (±11) years, and more than half were male (62%) and had a non-ischaemic aetiology for HF (59%). On average, LVEF was 0.33 (±0.14), with 67% of the patients having HF with depressed LVEF (<35%) and 33% of the patients having HF with "preserved" LVEF (≥35%). Hb was 8.4 (±1.2) mmol/l, eGFR was 54 (±20) ml/min/1.73 m2 and BMI was 26 (±5) kg/m2. At discharge, patients were classified as NYHA functional class II (48%), III (49%) or IV (3%), and were on medical therapy including diuretics (88%), ACE inhibitors/angiotensin II receptor blockers (71%), and beta-blockers (61%) (Table 1). Characteristics were not significantly different between patients with available BNP/NT-proBNP levels (n=541) and the total patient group included in the COACH study (n=1049).


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  		Table 1 Patient characteristics (n=541)

 
3.2. BNP and NT-proBNP levels
The median BNP value in the 541 patients with BNP and NT-proBNP available was 448 pg/ml, the interquartile range 209-916 pg/ml, the minimum value 14 pg/ml and the maximum value 5000 pg/ml. The median NT-proBNP value was 2599 pg/ml, the interquartile range 1314-5885 pg/ml, the minimum value 39 pg/ml and the maximum value 75,361 pg/ml (Table 1).

3.3. Anaemia
Haemoglobin levels were available in 528 of the 541 patients. BNP and NT-proBNP levels divided by quintiles of haemoglobin are presented in Fig. 1. Anaemia was present in 30% (n=159) of the 541 patients in which BNP and NT-proBNP levels were available. Of these 159 anaemic patients 114 (73%) also had renal dysfunction (eGFR <60 ml/min/1.73 m2) and of the 369 non-anaemic patients, 209 (57%) had renal dysfunction (Fig. 2).


Figure 01
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  		Fig. 1 BNP (A) and NT-proBNP (B) (95% CI) stratified by quintiles of haemoglobin.

 


Figure 02
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  		Fig. 2 BNP levels (A) and NT-proBNP levels (B) (95% CI) stratified by anaemia status and renal function. Anaemia was defined as Hb <7.5 mmol/l for women and Hb <8.1 mmol/l for men. Renal dysfunction was defined as eGFR <60 ml/min/1.73 m2.

 
3.4. Univariable determinants of BNP levels
Hb and eGFR were univariably related to the natural logarithm of BNP. Additionally, the following variables were potential confounders to these relationships (P<0.15): LVEF, NYHA functional class, Boston score, ischaemic/non-ischaemic aetiology of HF, pulmonary congestion, myocardial infarction before admission, systolic and diastolic blood pressure, haematocrit, BMI, prescribed diuretics at admission and at discharge (Table 2).


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  		Table 2 Univariable and multivariable regression coefficients

 
3.5. Multivariable determinants of BNP levels
The multivariable model was based on 428 patients with complete datasets. Hb and eGFR were independently related to the natural logarithm of BNP. Additionally, the multivariable model consisted of LVEF, the Boston score, BMI and prescribed diuretics at discharge. The R-square of the model was 0.20 (Table 2).

3.6. Univariable determinants of NT-proBNP levels
Hb and eGFR were univariably related to the natural logarithm of NT-proBNP. Additionally, the following variables were potential confounders to these relations (P<0.15): age, LVEF, NYHA functional class, Boston score, ischaemic/non-ischaemic aetiology of HF, pulmonary congestion, systolic and diastolic blood pressure, presence of pacemaker rhythm, hypertension, renal diseases, haematocrit, BMI, prescribed diuretics at admission and at discharge (Table 2).

3.7. Multivariable determinants of NT-proBNP levels
The multivariable model was based on 428 patients with complete datasets. Hb and eGFR were independently related to the natural logarithm of NT-proBNP levels. Furthermore, LVEF, the Boston score, BMI and prescribed diuretics at admission also added significant value to the multivariable linear regression model. The R-square of the model was 0.30 (Table 2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The major finding of the present study in a large sample of HF patients is that elevated levels of both BNP and NT-proBNP are associated with anaemia and renal dysfunction, independent of the severity of HF.

4.1. Anaemia and BNP/NT-proBNP levels
Anaemia is a common phenomenon in HF [23], and is related to the severity of disease [24]. Although BNP and NT-proBNP are also related to severity of HF, the negative association between both BNP and NT-proBNP and Hb, as found in the present study, cannot only be explained by the severity of HF. Hb was related to BNP and NT-proBNP levels independent of severity of HF as measured by both LVEF and the Boston score. The present findings are in agreement with the results of Willis et al. on 209 patients without HF or renal failure [13]. They found that Hb added significant value to the multivariable linear regression model of NT-proBNP determinants. Another study in patients with suspected coronary artery disease (n=234) also showed an independent association between Hb and BNP levels [25]. However, Wu et al. found no correlation between BNP levels and Hb in 200 patients with systolic HF, and only a small correlation was found between BNP and diastolic HF (n=121; r=0.047; P<0.05) [14]. The differences compared to our results might be explained by the exclusion of patients with renal dysfunction in the study by Wu et al. [14]. Since anaemia is often caused by renal insufficiency, a subgroup of HF patients without renal insufficiency does not fully represent HF patients in clinical practice and one might argue whether such a subgroup is the best to investigate the effect of anaemia on BNP levels.

The most obvious explanation for the independent associations of anaemia with BNP/NT-proBNP levels is that anaemia results in elevated plasma volume independent of severity of HF [11]. Since BNP and NT-proBNP are released in response to ventricular plasma overload [12] it is conceivable that BNP and NT-proBNP levels are higher in anaemic HF patients compared to non-anaemic HF patients. Additionally, patients with anaemia and renal dysfunction showed higher BNP and NT-proBNP levels, compared to anaemic patients without renal dysfunction. This can be explained by data from a previous study, where renal dysfunction was found to be a major cause of anaemia in HF patients, mediated by an erythropoietin production deficiency in the kidneys [15].

4.2. Renal function and BNP/NT-proBNP levels
Elevated levels of BNP were also independently related to renal dysfunction, and, although not directly compared, this relation seemed less powerful than the relation between renal dysfunction and NT-proBNP (–0.14 vs. –0.26 respectively). This difference may be explained by differences in clearance. NT-proBNP is probably mainly cleared from the blood by the kidneys [16], while BNP is most likely mainly cleared by neutral endopeptidases and natriuretic peptide clearance receptors [26,27]. This implies that the influence of renal dysfunction should be more pronounced on NT-proBNP levels compared to BNP levels.

4.3. Clinical setting
The diagnostic properties of BNP and NT-proBNP in dyspnoeic patients in an emergency department have been well described [1,2]. Additionally, recent data from our group showed that the well established BNP cut-off value of 100 pg/ml could also be used at discharge after admission for HF, to differentiate patients with different stages of HF severity and to distinguish systolic HF from diastolic HF [28]. However, co-existing anaemia may overstate the severity of HF at discharge. Therefore, anaemia should be taken into consideration during interpretation of BNP and NT-proBNP results at discharge.

4.4. Implications for clinical practice
First, our data indicate that anaemia and renal dysfunction should be taken into account when interpreting elevated levels of BNP and NT-proBNP. Although elevated natriuretic peptide levels could be related to worsening of heart failure, they can also be caused by anaemia or renal dysfunction, while the severity of HF remains unchanged. Second, it is well known that BNP and NT-proBNP have a large biological variation in patients with chronic heart failure [29]. Despite this, both anaemia and renal dysfunction remained highly significant independent predictors of increased levels of BNP and NT-proBNP. Third, the present study population does not reflect a general chronic HF population. Patients who have been admitted are generally more diseased, and have a greater risk of mortality and hospital re-admission. However, these findings may be of importance for monitoring the efficacy of therapy using BNP or NT-proBNP levels. Results of the BATTLESCARRED trial, which is currently ongoing [30], will provide further data on NT-proBNP guided treatment.

4.5. Conclusions
In this large group of hospitalised HF patients, lower haemoglobin levels and worse renal function were independently associated with elevated BNP and NT-proBNP levels. These results indicate that anaemia and renal dysfunction should be taken into consideration during interpretation of BNP and NT-proBNP levels in HF patients.


   Acknowledgements
 
The NHF-COACH study is financially supported by The Netherlands Heart Foundation (Grant 2000Z003). Prof. Van Veldhuisen is an Established Investigator of The Netherlands Heart Foundation (Grant D97.017). We are indebted to Roche Diagnostics (Mannheim, Germany) for providing NT-proBNP assay kits. We are grateful to Biosite Incorporated (San Diego, CA) for providing BNP assay kits, and to Novartis (Arnhem, the Netherlands) for an unrestricted grant to invest in BNP Triage® meters.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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